EP1409498B1 - Derives de phosphoglycane d'inositol et leurs utilisations en medecine - Google Patents

Derives de phosphoglycane d'inositol et leurs utilisations en medecine Download PDF

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Publication number
EP1409498B1
EP1409498B1 EP01928115A EP01928115A EP1409498B1 EP 1409498 B1 EP1409498 B1 EP 1409498B1 EP 01928115 A EP01928115 A EP 01928115A EP 01928115 A EP01928115 A EP 01928115A EP 1409498 B1 EP1409498 B1 EP 1409498B1
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Prior art keywords
compound
inositol
chiro
compounds
deoxy
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EP01928115A
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German (de)
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EP1409498A1 (fr
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Thomas William Rademacher
Hugo Norberto Caro
Irene Florey House FRANCOIS
Manuel Martin-Lomas
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Rodaris Pharmaceuticals Ltd
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Rodaris Pharmaceuticals Ltd
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Priority claimed from GB0011593A external-priority patent/GB0011593D0/en
Priority claimed from US09/798,004 external-priority patent/US6716826B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the present invention relates to compounds and their uses, and in particular to compounds which have a mimetic or antagonistic property of an inositol phosphoglycan or a free GPI precursor of an IPG, and the uses of these compounds, e.g. to treat a condition ameliorated by administration of an IPG second messenger or an IPG antagonist thereof.
  • IPG inositol phosphoglycan
  • IPGs mediate the action of a large number of growth factors including insulin, nerve growth factor, hepatocyte growth factor, insulin-like growth factor I (IGF-I), fibroblast growth factor, transforming growth factor ⁇ , the action of IL-2 on B-cells and T-cells, ACTH signalling of adrenocortical cells, IgE, FSH and hCG stimulation of granulosa cells, thyrotropin stimulation of thyroid cells, cell proliferation in the early developing ear and rat mammary gland.
  • IGF-I insulin-like growth factor I
  • fibroblast growth factor transforming growth factor ⁇
  • ACTH signalling of adrenocortical cells IgE, FSH and hCG stimulation of granulosa cells
  • thyrotropin stimulation of thyroid cells cell proliferation in the early developing ear and rat mammary gland.
  • IPGs Partially characterised inositolphosphoglycans
  • IGF-I insulin and insulin-like growth factor I
  • US Patent No: 6,004,938 discloses a group of synthetic inositol glycans having insulin-like action.
  • the compounds are based on 2-6 monsaccharide units linked to an inositol moiety.
  • the examples in the patent all employ myo -inositol and are composed of 5 or 6 units apart from two pseudo-trisaccharide compounds G and H.
  • Compounds G and H are HO-PO(H)O-6Man- ⁇ (1-4)-GluN- ⁇ (1-6)-(L)inositol-1.2(cyclic) phosphate and HO-PO(H)O-6Man- ⁇ (1-4)-GluN- ⁇ (1-6)-(L)inositol, otherwise known as O -(6-hydrogenphosphonate- ⁇ -D-mannopyranosyl)-(1-4)-(2-ammonio-2-deoxy- ⁇ -D-glucopyranosyl)-(1-6)-L- myo -inositol-1 ,2-cyclic phosphate and O -(6-hydrogenphosphonate- ⁇ -D-mannopyranosyl)-(1-4)-(2-amino-2-deoxy- ⁇ -D-glucopyranosyl)-L- myo -inositol.
  • the properties of exemplified compounds are investigated in lipogenesis and glucose transport assays employing rat fat
  • WO96/14075 discloses a generic family of compounds D-hexosamines linked to an inositol via a ⁇ 1,4-linkage.
  • the inositols can be myo or chiro-inositol or pinitol, while the hexosamines are glucosamine or galactosamine.
  • this application describes the synthesis of just two compounds 4- O -(2-deoxy-2-amino- ⁇ -D-galactopyranosyl)-D-pinitol and 4- O -(2-deoxy-2-ammo- ⁇ -D-galactopyranosyl)-D-chiro-inositol, or in IUPAC notation O -(2-amino-2-deoxy- ⁇ -D-galactopyranosyl)-(1-4)-D-pinitol and O -(2-amino-2-deoxy- ⁇ -D-galactopyranosyl)-(1-4)-D-chiro-inositol.
  • WO99/06421 (University of Virginia) describes synthetic insulin mimetic substances and includes a general formula I showing ⁇ 1,4-linked disaccharides. However, despite this the compounds synthesised in this application are exactly the same as those disclosed in the applicant's earlier application, WO96/14075 .
  • the present invention relates to IPG mimetic and antagonist compounds and to methods of producing the compounds and to their medical uses.
  • the compounds disclosed herein are useful as synthetic mimetics of IPG-P or IPG-A second messengers and/or growth factors whose action is mediated by IPGs, as synthetic mimetics of free GPI precursors or IPGs, or as competitive antagonists of IPGs.
  • the compounds are based on the 1,6 linkage of two or more sugar residues to a chiro-inositol.
  • the present invention provides a compound represented by the general formula: Y-X-1,6-chiro-inositol wherein:
  • the compounds may be provided as racemic or diasteromeric mixtures, resolved or partially resolved optical isomers, and as pharmaceutically acceptable salts, esters and derivatives as discussed in more detail below.
  • Examples of compounds within this embodiment of the invention are RGL1021, RGL1022, and compounds 19 and 25.
  • the X or Y sugar residue is a hexose or a pentose, and may be an aldose or a ketose.
  • the sugar residue can be a member of the D or L series and can include amino sugars, deoxy sugars and their uronic acid derivatives.
  • the sugar residue is a hexose
  • it is selected from the group consisting of glucose, galactose or mannose, or substituted hexose sugar residues such as an amino sugar residue such as hexosamine, galactosamine or glucosamine, and more preferably D-glucosamine (2-amino-2-deoxy-D-glucose) or D-galactosamine (2-amino-2-deoxy-D-galactose).
  • Preferred pentose sugar residues include arabinose, fucose and ribose.
  • the X or Y sugar residue is optionally substituted at one, two, three or four positions, other than the anomeric position or the position of linkage of the other radical or to the chiro-inositol.
  • the chiro-inositol may be in its D or L form, and is optionally substituted at one or more of the positions other than the position of linkage to the sugar radical.
  • the sugar radical is optionally substituted at one, two, three or four positions other than at the position of linkage to the inositol moiety (the anomeric position).
  • substituted groups include CF 3 , X(CH 2 ) n -O- (where X is hydrogen, or substituted or unsubstituted alkyl), CHF 2 O-.
  • the chro-inositol may have one or more of the hydroxyl groups through which the substituents described above are removed so that any substituent(s) are linked to the ring carbon atom.
  • the sugar residue is optionally substituted at one, two, three, or four positions other than at the position of linkage to the inositol moiety.
  • the X and Y sugar residues are linked to each other via a 1,1 linkage, 1,2 linkage, 1,3 linkage, 1, 4 linkage or 1,6 linkage.
  • the linkage between the units may be an a or ⁇ linkage.
  • the linkage of the X sugar residue to the chiro-inositol is a 1,6 linkage via one of the oxygen atoms of the chiro-inositol moiety. However, this oxygen atom can be replaced one or more times by -CH 2 - or -S- groups.
  • the present invention provides a compound, or a substituted form thereof as defined above, selected from the group consisting of:
  • the present invention provides methods for making the compounds of the invention or their intermediates as set out in the following experimental description and the schemes.
  • the present invention further relates to compounds which are the novel intermediates described herein.
  • the present invention provides one or more of the above compounds for use in a method of medical treatment.
  • the compounds may be useful as IPG mimetics or IPG antagonists, e.g. as competitive antagonists.
  • the present invention provides the use of one or more of the above compounds for the preparation of a medicament for the treatment of a condition ameliorated by the administration of an inositol phosphoglycan (IPG) second messenger or an IPG antagonist.
  • IPG inositol phosphoglycan
  • Examples of such conditions are set out in the pharmaceutical uses section below.
  • IPGs Inositol phosphoglycans
  • IPG-A mediators modulate the activity of a number of insulin-dependent enzymes such as cAMP dependent protein kinase (inhibits), adenylate cyclase (inhibits) and cAMP phospho-diesterases (stimulates).
  • IPG-P mediators modulate the activity of insulin-dependent enzymes such as pyruvate dehydrogenase phosphatase (stimulates) and glycogen synthase phosphatase (stimulates).
  • the A-type mediators mimic the lipogenic activity of insulin on adipocytes, whereas the P-type mediators mimic the glycogenic activity of insulin on muscle.
  • Both A-and P-type mediators are mitogenic when added to fibroblasts in serum free media.
  • the ability of the mediators to stimulate fibroblast proliferation is enhanced if the cells are transfected with the EGF-receptor.
  • A-type mediators can stimulate cell proliferation in the chick cochleovestibular ganglia.
  • Soluble IPG fractions having A-type and P-type activity have been obtained from a variety of animal tissues including rat tissues (liver, kidney, muscle, brain, adipose, heart) and bovine liver. IPG-A and IPG-P biological activity has also been detected in human liver and placenta, malaria parasitized RBC and mycobacteria. The ability of an anti-inositolglycan antibody to inhibit insulin action on human placental cytotrophoblasts and BC3H1 myocytes or bovine-derived IPG action on rat diaphragm and chick cochleovestibular ganglia suggests cross-species conservation of many structural features. However, it is important to note that although the prior art includes these reports of IPG-A and IPG-P activity in some biological fractions, the purification or characterisation of the agents responsible for the activity is not disclosed.
  • IPG-A substances are cyclitol-containing carbohydrates, also containing Zn 2+ ions and phosphate and having the properties of regulating lipogenic activity and inhibiting cAMP dependent protein kinase. They may also inhibit adenylate cyclase, be mitogenic when added to EGF-transfected fibroblasts in serum free medium, and stimulate lipogenesis in adipocytes.
  • IPG-P substances are cyclitol-containing carbohydrates, also containing Mn 2+ and/or Zn 2+ ions and phosphate and having the properties of regulating glycogen metabolism and activating pyruvate dehydrogenase phosphatase. They may also stimulate the activity of glycogen synthase phosphatase, be mitogenic when added to fibroblasts in serum free medium, and stimulate pyruvate dehydrogenase phosphatase.
  • Protocols for determining characteristic IPG biological activities such as PDH activation, PKA inhibition, acetylCoA activation, fructose-1,6-bis-phosphatase activity and lipogenesis are well known in the art, e.g. as described in Caro et al [14] .
  • the compounds of the invention may be derivatised in various ways.
  • derivatives of the compounds includes salts, coordination complexes with metal ions such as Mn 2+ and Zn 2+ , esters such as in vivo hydrolysable esters, free acids or bases, hydrates or glycolipid derivatives.
  • Salts of the compounds of the invention are preferably physiologically well tolerated and non toxic. Many examples of salts are known to those skilled in the art.
  • Compounds having acidic groups such as phosphates or sulfates, can form salts with alkaline or alkaline earth metals such as Na, K, Mg and Ca, and with organic amines such as triethylamine and Tris (2-hydroxyethyl)amine.
  • Salts can be formed between compounds with basic groups, e.g. amines, with inorganic acids such as hydrochloric acid, phosphoric acid or sulfuric acid, or organic acids such as acetic acid, citric acid, benzoic acid, fumaric acid, or tartaric acid.
  • Compounds having both acidic and basic groups can form internal salts.
  • Esters can be formed between hydroxyl or carboxylic acid groups present in the compound and an appropriate carboxylic acid or alcohol reaction partner, using techniques well known in the art.
  • prodrugs of the compounds are convertible in vivo or in vitro into one of the parent compounds.
  • at least one of the biological activities of compound will be reduced in the prodrug fonn of the compound, and can be activated by conversion of the prodrug to release the compound or a metabolite of it.
  • prodrugs are glycolipid derivatives in which one or more lipid moieties are provided as substituents on the sugar residue or the chiro-inositol moieties, leading to the release of the free form of the compound by cleavage with a phospholipase enzyme.
  • the compounds described herein or their derivatives can be formulated in pharmaceutical compositions, and administered to patients in a variety of forms, in particular to treat conditions which are ameliorated by the administration of inositol phosphoglycan second messengers or IPG antagonists such as competitive antagonist.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may include a solid carrier such as gelatin or an adjuvant or an inert diluent.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Such compositions and preparations generally contain at least 0.1 wt% of the compound.
  • Parental administration includes administration by the following routes: intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraocular, transepithelial, intraperitoneal and topical (including dermal, ocular, rectal, nasal, inhalation and aerosol), and rectal systemic routes.
  • intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • suitable solutions using, for example, solutions of the compounds or a derivative thereof, e.g. in physiological saline, a dispersion prepared with glycerol, liquid polyethylene glycol or oils.
  • compositions can comprise one or more of a pharmaceutically acceptable excipient, carrier, buffer, stabiliser, isotonicizing agent, preservative or anti-oxidant or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material may depend on the route of administration, e.g. orally or parentally.
  • Liquid pharmaceutical compositions are typically formulated to have a pH between about 3.0 and 9.0, more preferably between about 4.5 and 8.5 and still more preferably between about 5.0 and 8.0.
  • the pH of a composition can be maintained by the use of a buffer such as acetate, citrate, phosphate, succinate, Tris or histidine, typically employed in the range from about 1 mM to 50 mM.
  • the pH of compositions can otherwise be adjusted by using physiologically acceptable acids or bases.
  • Preservatives are generally included in pharmaceutical compositions to retard microbial growth, extending the shelf life of the compositions and allowing multiple use packaging.
  • preservatives include phenol, meta-cresol, benzyl alcohol, para-hydroxybenzoic acid and its esters, methyl paraben, propyl paraben, benzalconium chloride and benzethonium chloride.
  • Preservatives are typically employed in the range of about 0.1 to 1.0 % (w/v).
  • the pharmaceutically compositions are given to an individual in a "prophylactically effective amount” or a “therapeutically effective amount” (as the case may be, although prophylaxis may be considered therapy), this being sufficient to show benefit to the individual. Typically, this will be to cause a therapeutically useful activity providing benefit to the individual.
  • the actual amount of the compounds administered, and rate and time-course of administration, will depend on the nature and severity of the condition being treated. Prescription of treatment, e.g. decisions on dosage etc, is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners.
  • compositions are preferably administered to patients in dosages of between about 0.01 and 100mg of active compound per kg of body weight, and more preferably between about 0.5 and 10mg/kg of body weight.
  • composition may further comprise one or more other pharmaceutically active agents, either further compounds of the invention, inositol phosphoglycans, growth factors such as insulin, NGF or other growth factors listed below, or other drugs, e.g. those in use for the treatment of diabetes or other conditions set out below.
  • other pharmaceutically active agents either further compounds of the invention, inositol phosphoglycans, growth factors such as insulin, NGF or other growth factors listed below, or other drugs, e.g. those in use for the treatment of diabetes or other conditions set out below.
  • IPGs are second messengers for a range of different growth factors and hormones, including insulin, nerve growth factor, hepatocyte growth factor, endothelial growth factor, insulin-like growth factor I (IGF-I), fibroblast growth factor, transforming growth factor ⁇ , the action of IL-2 on B-cells and T-cells, ACTH signalling of adrenocortical cells, IgE, FSH and hCG stimulation of granulosa cells, thyrotropin stimulation of thyroid cells, cell proliferation in the early developing ear and rat mammary gland. Consequently, IPGs or their antagonists can be used in the treatment or amelioration of disorders mediated by the growth factors or to mimic specific growth factor or hormone biological activities.
  • IGF-I insulin-like growth factor I
  • fibroblast growth factor transforming growth factor ⁇
  • ACTH signalling of adrenocortical cells IgE, FSH and hCG stimulation of granulosa cells
  • IPGs or IPG antagonists examples include, diabetes, obesity, dyslipidaemia, pre-eclampsia, neurotrophic disorders, hepatic damage and adrenal atrophy.
  • WO98/10791 discloses that pre-eclampsia is characterised by elevated levels of IPG-P and that it can be treated using an IPG-P antagonist.
  • Compounds of the invention which are IPG-P antagonists, e.g. antagonists which compete with wild-type IPG-P but lack one or more of its activities, could be used in the treatment of pre-eclampsia.
  • IPG-P and IPG-A and IPG-A antagonists in the diagnosis and treatment of diabetes is disclosed in WO98/11435 .
  • This application discloses that in some forms of diabetes the ratio of P:A-type IPGs is imbalanced and can be corrected by administering a medicament containing an appropriate ratio of IPG-P, IPG-A or antagonist(s) thereof.
  • NIDDM obese type II diabetes
  • IDDM body mass index ⁇ 27
  • body mass index ⁇ 27 body mass index ⁇ 27
  • the compounds and compositions of the present invention can be employed in such types of treatment. More particularly, the compounds are likely to be of use in the treatment of various form of diabetes and diabetic complications including diabetes due to insulin resistance, insulin resistance in type I diabetes and brittle diabetes, obese or lean type II diabetes, and of conditions associated with insulin resistance or insulin underproduction, such as neurotrophic disorders or polycystic ovary syndrome, lipodystrophy, age-related memory loss, and post-ischaemic damage secondary to stroke or post-transplant complications.
  • the compounds of this invention are also likely to be of use in controlling neuron proliferation or neurite outgrowth, either in vitro or in vivo, e.g. acting as a nerve or neurite growth factor mimetic second messenger. They may thus have applications in the treatment and/or diagnosis of any condition related to neuron proliferation or neurite differentiation.
  • WO99/38516 discloses that IPG-A and synthetic mimetics thereof cause neuron proliferation, mimicking the action of the growth factor IGF-I.
  • IPG-P and synthetic mimetics thereof such as compound C4 cause neurite outgrowth.
  • the neurons may be central (brain and spinal cord) neurons, peripheral (sympathetic, parasympathetic, sensory and enteric) neurons, e.g.
  • Treatments may involve the treatment of damage to nerve, spinal cord or central nervous system damage secondary to trauma, or autoimmune or metabolic damage, or post-ischaemic damage secondary to stroke or post-transplant complications, motor neuron disease, neurodegenerative disorders or neuropathy.
  • Damage to the nervous system includes the results of trauma, stroke, surgery, infection (e.g. by viral agents), ischemia, metabolic disease, toxic agents, or a combination of these or similar causes.
  • Motor neuron disease includes conditions involving spinal muscular atrophy, paralysis or amyotrophic lateral sclerosis.
  • Neurodegenerative disorders include Parkinson's disease, Alzheimer's disease, epilepsy, multiple sclerosis, Huntingdon's chorea and Meniere's disease.
  • the compounds of the invention may also be useful as hepatocyte growth factor mimetic second messengers, e.g. in the preparation of medicaments for the treatment of hepatic damage caused by infection, alcohol abuse, drug sensitivity, or autoimmunity.
  • the compounds may also be useful as fibroblast growth factor mimetic second messengers or epidermal growth factor mimetic second messengers, e.g. in the preparation of medicaments for the promotion of wound healing following surgery or trauma or tissue damage induced by ischaemia or autoimmunity.
  • the compounds of the invention may be useful as adrenal cell growth factor mimetic second messengers or ACTH mimetic second messengers in the preparation of a medicament for the treatment of disease states involving adrenal atrophy.
  • the compounds of the invention can readily be tested using the assays identified herein to determine their suitability for some or all of the medical uses described above. Thus, even compounds with a relatively low activity in one of the enzymes assays disclosed herein, may be useful by virtue of possessing a different activity, and moreover the pattern of activities can be used to rapidly screen the compounds for suitability in the various medical applications disclosed herein.
  • Activity Diabetes I Diabetes II Obesity Alzheimer's Neurotrophics PDH Kinase Inhibit Inhibit No Effect Inhibit No effect PDH Phosphatase Activate Activate No effect No effect No effect No effect No effect No effect Acetyl CoA carboxylase I * Activate No effect No effect No effect No effect No effect No effect No effect No effect No effect No effect * found in liver and adipose cytosol.
  • Phosphoryl groups such as phosphate, cyclic phosphate or substituted phosphate or cyclic phosphate can be substituted into the compounds of the invention by the phosphate or phosphoramidite method, Bannwath et al, Helvetica Chemica Acta, 70:175-186, 1987 and Yu & Fraser-Reid, Tetrahedron Lett., 29:979-982, 1988 .
  • Phosphate protecting groups can also be synthesized according to the methods disclosed in Hoeben-Weyl, Methods of Organic Chemistry, volume 12/1 or 12/2 , Molheimer, Synthetic Methods of Organic Chemistry, Vol 45 .
  • Protecting groups for the OH of sugars include menthoxycarbonyl (MntCO), acetal (in particular, two R groups may together represent a bridging acetal such as O-cyclohexylidene, O- isopropylidene or O-benzylidene), tert -butyldimethylsilyl (TBDMS), benzyl (Bn), tert -butyldiphenylsilyl (TBDPS).
  • MntCO menthoxycarbonyl
  • acetal in particular, two R groups may together represent a bridging acetal such as O-cyclohexylidene, O- isopropylidene or O-benzylidene
  • TDMS tert -
  • the compounds of the invention can be tested for one or more the characteristic IPG-P and/or IPG-A activities mentioned above to determine whether they will be suitable for use a IPG mimetics or antagonists.
  • Preferred assays measure the effect of the compounds on PDH phosphatase, PKA or lipogenesis. Protocols for these assays are provided in Caro et al [14] .
  • the compounds can also be tested to determine whether they activate or inhibit other enzymes involved in insulin signalling mechanism, such as glucose-6-phosphatase.
  • Routine NMR spectra were recorded with Bruker Avance DPX300 ( 1 H, 300 MHz), Bruker Avance DRX400 ( 1 H, 400 MHz), and Bruker Avance DRX500 ( 1 H, 500 MHz) spectrometers. Chemical shifts are reported in ppm, and coupling constants are reported in Hz. Spectra were referenced to the residual proton or carbon signals of the solvent. High-resolution mass spectra were recorded on a Kratos MS-80RFA 241-MC apparatus. Optical rotations were determined with a Perkin-Elmer 341 polarimeter. Elemental analyses were performed using a Leco CHNS-932 apparatus. The organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo.
  • pseudopentasaccharide 25 was carried out following the strategy indicated in Schemes 5(I) and 5(II). Condensation of the trisaccharide trichloroacetimidate 20 with acceptor 4 afforded the pseudopentasaccharide derivative 21 in reasonable yield. Removal of the pivaloyl group in 21 followed by conventional benzylation yielded compound 22 in quantitative yield. Deallylation of 22 (Scheme 5(II)) gave 23 phosphorylation of which yielded 24. Final catalytic hydrogenation of 24 gave rise to the pseudopentasaccharide 25.

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Claims (12)

  1. Composé représenté par la formule générale :

            Y-X-1,6-chiro-inositol

    dans laquelle :
    X représente un radical de sucre ;
    Y représente un à trois radicaux de sucre ;
    le résidu de sucre est non substitué ou substitué par un à quatre groupes, et le cyclitol est non substitué ou est en outre substitué par un à quatre groupes, le groupe ou les groupes étant indépendamment choisis parmi :
    (a) un groupe phosphoryle, qui est un phosphate -O-P-(O)(OH)2 ; un thiophosphate -O-P(S)(OH)2 ; des esters de phosphate -O-P(O)(OR)2 ; des esters de thiophosphate -O-P(S) (OR)2 ; un phosphonate -O-P (O) OHR ; un thiophosphonate -O-P(S)OHR ; un phosphonate substitué -O-P(O)OR1R2 ; un thiophosphonate substitué -O-P (S) OR1R2 -O-P (S) (OH) (SH) ; ou un phosphate cyclique ;
    (b) un composé contenant du phosphore qui est un phosphoramidite -O-P(OR)-NR1R2 ou un phosphoramidate -O-P(O)(OR)-NR1R2 ;
    (c) un groupe soufré qui est -O-S(O)(OH), -SH, -SR, -S(-O)-R, -S(O)2R,RO-S(O)2, -O-SO2NH2, -O-SO2R1R2 ou un sulfamide -NHSO2NH2;
    (d) un groupe amino qui est -NHR, -NR1R2, -NHAc, -NHCOR, -NH-O-COR, -NHSO3, - NHSO2R ou -N(SO2R)2, et/ou un groupe amidino qui est -NH-C(=NH)NH2 et/ou un groupe uréido qui est -NH-CO-NR1R2 ou un groupe thiouréido qui est -NH-C(S)-NH2 ;
    (e) un groupe hydroxy ou un groupe hydroxy substitué qui est -OR3, où R3 est un groupe alkyle en C1 à 10 non substitué ou substitué, par exemple CHF2 ou CF3, alcoxyalkyle, aryloxyalkyle, cycloalkyle, alcényle (alkyle substitué), alkylène (cycloalkyle en C3 à 7), -OCOR, aryle, hétéroaryle, acétal, ou bien où deux groupes hydroxyle sont joints sous forme de cétal ;
    (f) un substituant halogène, qui est le fluor ou le chlore ;
    (g) un atome d'hydrogène, pour former un désoxyose;
    dans lesquels R, R1 et R2 sont indépendamment un atome d'hydrogène ou un groupe alkyle ou aryle en C1 à 10 non substitué ou substitué ;
    ou un sel, un complexe de coordination avec des ions de métaux, un ester, un acide ou une base libre, un hydrate de celui-ci, ou un dérivé glycolipide dans lequel une fraction lipide pouvant être clivée par une enzyme phospholypase est un substituant d'un résidu de sucre ou du cyclitol.
  2. Composé selon la revendication 1, dans lequel le résidu de sucre et le chiro-inositol sont liés en α.
  3. Composé selon la revendication 1, dans lequel le résidu de sucre et le chiro-inositol sont liés en β.
  4. Composé selon l'une quelconque des revendications précédentes, dans lequel le résidu de sucre est un hexose ou un pentose, ou des formes substituées de ceux-ci.
  5. Composé selon la revendication 4, dans lequel le résidu de sucre est un hexose choisi dans le groupe constitué par le glucose, le galactose ou le mannose.
  6. Composé selon la revendication 4, dans lequel le résidu de sucre est une hexosamine.
  7. Composé selon la revendication 6, dans lequel l'hexosamine est la galactosamine ou la glucosamine.
  8. Composé selon l'une quelconque des revendications précédentes, dans lequel le chiro-inositol est un énantiomère D ou L.
  9. Composé selon l'une quelconque des revendications précédentes, qui est :
    RGL1021 O-(D-galactopyranosyl)-α(1,4)-O-(2'-amino-2'-désoxy-D-glucanopyranosyl)-α(1,6)-chiro-inositol ;
    RGL1022 O-(D-galactopyranosyl)-α(1,4)-O-(2'-amino-2'-désoxy-D-glucanopyranosyl)-α(1,6)-chiro-inositol-1-phosphate ;
    Composé 25 O-α-D-mannopyranosyl-(1,2)-O-α-D-mannopyranosyl-(1,6)-O-α-D-mannopyranosyl-(1,4)-O-2 ammonio-2-désoxy-α-D-glucopyranosyl-(1,6)-D-chiro-inositol-1-phosphate ; et
    Composé 19 O-β-D-galactopyranosyl-(1,4)-2-ammonio-2-désoxy-α-D-galactopyranosyl-(1,6)-D-chiro-inositol-1-phosphate ;
    ou un sel, un complexe de coordination avec des ions de métaux, un ester, un acide ou une base libre, un hydrate de celui-ci, ou un dérivé glycolipide dans lequel une fraction lipide pouvant être clivée par une enzyme phospholipase est un substituant d'un résidu de sucre ou du cyclitol.
  10. Composition comprenant un composé selon l'une quelconque des revendications précédentes, en combinaison avec un support pharmaceutiquement acceptable.
  11. Composé selon l'une quelconque des revendications 1 à 9, à utiliser en thérapie.
  12. Utilisation d'un composé selon l'une quelconque des revendications 1 à 9, pour la préparation d'un médicament destiné au traitement d'une affection améliorée par l'administration d'un second messager d'inositol phosphoglycane (IPG) ou d'un antagoniste d'IPG.
EP01928115A 2000-05-12 2001-05-11 Derives de phosphoglycane d'inositol et leurs utilisations en medecine Expired - Lifetime EP1409498B1 (fr)

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Application Number Priority Date Filing Date Title
US20359800P 2000-05-12 2000-05-12
US203598P 2000-05-12
GB0011593 2000-05-12
GB0011593A GB0011593D0 (en) 2000-05-12 2000-05-12 Compounds and their uses
US798004 2001-03-02
US09/798,004 US6716826B2 (en) 2000-05-12 2001-03-02 Compounds and their uses
PCT/GB2001/002098 WO2001085745A1 (fr) 2000-05-12 2001-05-11 Derives de phosphoglycane d'inositol et leurs utilisations en medecine

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EP1409498B1 true EP1409498B1 (fr) 2008-03-26

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US7943594B2 (en) * 2002-07-10 2011-05-17 Massachusetts Institute Of Technology Solid-phase and solution-phase synthesis of glycosylphosphatidylinositol glycans
JPWO2016076310A1 (ja) * 2014-11-10 2017-08-17 昭和電工株式会社 保湿剤

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JPH0649715B2 (ja) * 1987-02-10 1994-06-29 栗田工業株式会社 末端にイノシト−ル残基を結合したグルコオリゴ糖およびその製造方法
JPH03237101A (ja) * 1989-12-18 1991-10-23 Rikagaku Kenkyusho グリコシルフォスファチジルイノシトールアンカー合成中間体及びグリコシルフォスファチジルイノシトールアンカー類縁体の合成中間体
JPH04120089A (ja) * 1990-09-11 1992-04-21 Rikagaku Kenkyusho グリコシルフォスファチジルイノシトールアンカー合成中間体
JPH06293790A (ja) * 1993-04-08 1994-10-21 Kyowa Hakko Kogyo Co Ltd 生理活性物質イノシトールグリカン
GB9618931D0 (en) * 1996-09-11 1996-10-23 Univ London Inositol phosphoglycans for therapeutic use in pre-eclampsia and diabetes
DE19649350A1 (de) * 1996-11-28 1998-06-04 Hoechst Ag Inositolglykane mit insulinartiger Wirkung
CA2236641C (fr) * 1997-05-07 2008-07-15 Cornell Research Foundation, Inc. Preparation de fagopyritols et utilisations correspondantes
GB9801899D0 (en) * 1998-01-29 1998-03-25 Univ London Neurotrophic properties of ipgs analogues
AUPP589398A0 (en) * 1998-09-14 1998-10-08 Walter And Eliza Hall Institute Of Medical Research, The Immunogenic compositions and uses thereof

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WO2001085745A1 (fr) 2001-11-15
DE60133421D1 (de) 2008-05-08
CA2433857C (fr) 2012-07-31
EP1409498A1 (fr) 2004-04-21
AU2001254979A1 (en) 2001-11-20
ATE390434T1 (de) 2008-04-15

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